Indanes and analgesic compositions and methods thereof

ABSTRACT

A compound selected from the group consisting of enantiomers and diastereoisomer forms and mixtures thereof of the formula   &lt;IMAGE&gt; I

PRIOR APPLICATION

This application is a division of U.S. patent application Ser. No.086,996 filed Aug. 19, 1987.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel indanes of formulaI and their non-toxic, pharmaceutically acceptable acid addition saltsand a novel process and intermediates for their preparations.

It is another object of the invention to provide novel central analgesiccompositions and a novel method of inducing central analgesic activityin warm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the groupconsisting of enantiomers and diastereoisomer forms and mixtures thereofof the formula ##STR2## wherein R₆ is selected from the group consistingof hydrogen, halogen and alkyl and alkoxy of 1 to 5 carbon atoms, R₁ andR₂ are individually hydrogen or alkyl of 1 to 5 carbon atoms or takentogether with the carbon atoms to which they are attached form acycloalkyl of 3 to 6 carbon atoms optionally containing a heteroatomselected from the group consisting of --S--, --O-- and --N--, one of Aand B has the formula ##STR3## and the other has the formula ##STR4## Ris selected from the group consisting of hydrogen and alkyl of 1 to 5carbon atoms, Z is selected from the group consisting of --(CH₂)_(n) --,branched alkylene of 2 to 8 carbon atoms and --CH₂ O--, n is an integerof 0 to 5, X, X' and X" are individually selected from the groupconsisting of hydrogen, alkyl and alkoxy of 1 to 4 carbon atoms,halogen, --OH, --CF₃, --NO₂, --NH₂, mono and dialkylamino of 1 to 4alkyl carbon atoms and sulfamino, R₃ and R₄ are individually selectedfrom the group consisting of hydrogen and alkyl of 1 to 5 carbon atomsor taken together with the nitrogen atom to which they are attached forma 5 to 6 member heterocycle optionally containing a member of the groupconsisting of --O--, --S-- and ##STR5## R₁ ' is hydrogen or alkyl of 1to 4 carbon atoms and their non-toxic, pharmaceutically acceptable acidaddition salts.

When R₁, R₂, R₃, R₄, R₆, R, X, X' and X" are alkyl, they are preferablymethyl, ethyl n-propyl or isopropyl but may also be n-butyl, isobutyl orn-pentyl. Examples of cycloalkyl formed by R₁ and R₂ and the carbonatoms to which they are attached are cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Examples of the cycloalkyl containing anoxygen, sulfur or nitrogen in the ring are tetrahydropyran,tetrahydrothiapyran and piperidinyl.

When Z is --(CH₂)_(n) --, n is preferably 0 or 1 and when Z is abranched alkylene, it is preferably alkylene substituted with methyl orethyl such as 1,1-ethanediyl, methyl-1-ethanediyl-1,2, methyl-1 or-2-propanediyl-1,2 and ethyl-1-ethanediyl-1,2.

When R₆, X, X' and X" are alkoxy, they are preferably methoxy or ethoxybut they may be other alkoxys such as propoxy, isopropoxy and linear andbranched butoxy and when they are halogen, they are preferably chlorinebut may be fluorine, iodine or bromine. When X, X' and X" aremonoalkylamino or dialkylamino, the alkyls are preferably methyl orethyl.

Examples of heterocycles formed by R₃ and R₄ and the nitrogen to whichthey are attached are pyridinyl, piperazinyl, methylpiperazinyl,ethylpiperazinyl, propylpiperazinyl, piperidinyl, morpholinyl andpyrrolidinyl.

Examples of suitable acids to form the non-toxic, pharmaceuticallyacceptable acid addition salts are inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acidand organic acids such as formic acid, acetic acid, propionic acid,maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid,oxalic acid, glyoxylic acid and aspartic acid, alkanesulfonic acids,such as methanesulfonic acid, arylsulfonic acids such as benzenesulfonic acid and arylcarboxylic acids such as benzoic acid.

Among the preferred compounds of formula I are those wherein A and Bhave the trans configuration, those wherein ##STR6## has R₃ and R₄ bothas methyl or together with the nitrogen form pyrrolidine, piperidine, orpiperazine optionally substituted with alkyl of 1 to 3 carbon atoms,those in which ##STR7## has R as hydrogen, methyl, or ethyl, Z is --CH₂O--. ##STR8## or --(CH₂)_(n) -- and n is 0 or 1, those wherein R₁ and R₂are both hydrogen or methyl or together with the carbon atoms formtetrahydropyran and those wherein X, X' and X" are individually selectedfrom the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy,--NO₂, sulfamino --CF₃ or chlorine and their non-toxic, pharmaceuticallyacceptable acid addition salts.

Examples of specific preferred compounds of formula I are

[trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamide,

[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-3-nitro-benzene-acetamide,

[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-nitro-benzene-acetamide,

[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-(4-trifluoromethyl)-benzene-acetamide,

[trans(±)]2-(3,4-dichlorophenoxy)-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-acetamide,

[trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(dimethylamino)-1H-inden-1-yl]-N-methyl-benzene-acetamide,

[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-nitro-benzene-acetamide(isomer A), and their non-toxic, pharmaceutically acceptable acidaddition salts.

The novel process of the invention for the preparation of the compoundsof formula I wherein A and B have the trans configuration comprisesreacting a compound of the formula ##STR9## wherein R₆, R₁ and R₂ havethe above definition with a compound of the formula ##STR10## wherein Rhas the above definition and R₅ is an amine protective group, preferablybenzyl to obtain a compound of the formula ##STR11## the hydroxy groupis activated and reacted with an amine of the formula ##STR12## whereinR₃ and R₄ have the above definitions to obtain a compound of the formula##STR13## removing the R₅ group to obtain a compound of the formula##STR14## reacting the latter with an acid or a functional derivativethereof of the formula ##STR15## wherein Z, X, X' and X" have the abovedefinitions to obtain a compound of formula I wherein A is ##STR16## andR is ##STR17## or the compound of formula II is reacted with an amine ofthe formula ##STR18## to form a compound of the formula ##STR19##activating the hydroxyl of the latter and reacting with an amine of theformula

    NH.sub.2 --R                                               X

wherein R has the above definitions to obtain a compound of the formula##STR20## and reacting the latter with an acid of formula VIII or afunctional derivative thereof to obtain a compound of formula I whereinA is ##STR21## and B is ##STR22## and optionallly resolving the latterand/or forming the acid addition salts thereof.

Preferably, the hydroxyl functions of formulae IV and IX are activatedwith methanesulfonyl chloride and the protective group R₅ of formula VIis benzyl which can be removed by catalytic hydrogenation in thepresence of a palladium catalyst. The activation of the hydroxyl of thecompounds of formula VIII is effected in the presence ofcarbonyldiimidazole and the acids of formula VIII are used in the acidchloride or mixed anhydride form. The resolution of the compounds offormula I can be effected by known methods.

The process of the invention to form the compounds of formula I whereinA and B have the cis configuration may be prepared by the followingreaction scheme: ##STR23## The compounds with the formula (I) as definedabove as well as their addition salts with acids show usefulpharmacological properties. They show in particular a strong affinityfor the opiate receptors and in particular for the K receptors and areendowed with central analgesic properties.

They are also endowed with diuretic properties and anti-arrythmic,anti-cerebral, ischaemic and hypotensive properties.

The novel central analgesic compositions of the invention are comprisedof a central analgesically effective amount of at least one compound offormula I and their non-toxic, pharameutically acceptable acid additionsalts and an inert pharmaceutical carrier or excipient.

The compositions are useful for the treatment of pain of any origin suchas muscular, articular or nervous pain. They are also useful in thetreatment of dental pains, migraines, herpes, in the treatment ofintense pains, in particular those resistant to peripheral antalgics,for example in the course of a neoplastic process, in the treatment ofpancreatitis, nephritic or biliar colics, in the treatment ofpost-operative and post-traumatic pains.

The subject matter of the invention is also the novel diurecticcompositions which comprise at least one compound of formula I and itsnon-toxic pharmaceutically acceptable acid and addition salts andquaternary ammonium salts and an inert pharmaceutical carrier orexcipient.

The compositions may also be used in the treatment of oedematoussyndromes, of cardiac insufficiency, of certain obesities, of cirrhoses,in the treatment of severe and refractory oedemas, in particular thosefrom congestive cardiac insufficiency and in the long term treatment ofarterial hypertension.

The subject matter of the invention is also the novel anti-arrythmiccompositions which comprise at least one compound of formula I and itsnon-toxic pharmaceutically acceptable acid addition salts and quaternaryammonium salts and an inert pharmaceutical carrier or excipient.

The compositions can be used in the treatment of ventricular,supraventricular and functional arrythmias.

The compositions may be in the form of tablets, dragees, gelules,granules, suppositories, creams, ointments, gels, aerosols andinjectable solutions or suspensions.

Examples of suitable excipients are talc, gum arabic, lactose, starch,magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fattysubstances of animal or vegetable origin, paraffin derivatives, glycols,various wetting, dispersing or emulsifying agents and preservatives.

Particularly preferred compositions of the invention contain as theactive compounds a member of the group consisting of

[trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamide,

[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-3-nitro-benzene-acetamide,

[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-nitro-benzene-acetamide,

[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-(4-trifluoromethyl)-benzene-acetamide,

[trans(±)]2-(3,4-dichlorophenoxy)-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-acetamide,

[trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(dimethylamino)-1H-inden-1-yl]-N-methyl-benzeneacetamide and

[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-nitro-benzene-acetamide(isomer A) and their non-toxic, pharmaceutically acceptable acidaddition salts.

The novel method of relieving pain in warm-blooded animals, includinghumans, comprises administering to warm-blooded animals a centralanalgesically effective amount of at least one compound of formula I andtheir non-toxic, pharmaceutically acceptable acid addition salts. Thecompounds may be administered orally, rectally or parenterally and theusual daily dose is 0.05 to 6 mg/kg depending on the condition treated,the method of administration and the specific compound.

The novel method of inducing diuresis in warm-blooded animals includinghumans, comprises administering to warm-blooded animals a diureticallyeffective amount of at least one compound of formula I and itsnon-toxic, pharmaceutically acceptable acid addition salts andquaternary ammonium salts. The compound may be administered orallyrectally or parenterally and the usual daily dose is 1 γ to 1 mg/kgdepending on the condition treated, the specific compound and method ofadministration. For example a daily oral dose of 10 to 1 mg/kg and adaily parenteral dose of 1 γ to 100 γ/kg are useful for diureticactivity, more particularly a daily oral dose of 10 γ to 100 γ/kg and adaily parenteral dose 5 γ to 50 γ/kg.

The novel method of treating arrythmia in warm blooded animals includinghumans, comprises administering to warm-blooded animals aantiarythmically effective amount of at least one compound of formula Iand its non-toxic, pharmaceutically acceptable acid addition salts andquaternary ammonium salts. The compounds may be administered preferablyorally, rectally or parenterally and the usual daily dose is 1 to 10mg/kg depending on the condition treated, the specific compound andmethod of administration.

For example, the daily oral dose for the treatment of ventricular,supraventricular and junctional arrythmias is 1 to 10 mg/kg.

The starting compounds of formula II wherein R₁ and R₂ are hydrogen oralkyl of 1 to 5 carbon atoms may be prepared by oxidation of thecorresponding indene. The other compounds of formula II, especiallywherein R₁ and R₂ form tetrahypropyran may be prepared by the followingreaction: ##STR24##

The novel intermediates of the invention are the compounds of formulaeIV, VI, VII, IX and XI wherein R₆ is other than hydrogen.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE 1[Trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamideand its hydrochloride STEP A:[trans(±)]2,3-dihydro-1-(1-pyrrolidinyl)-1H-inden-2-ol

10.8 ml of pyrrolidine in 6.75 g of 2,3-epoxy-indane [described byMousseron et al. Bulletin de la Societe Chimique de France, 1946, p.629-630] in 10.8 ml of demineralized water. The temperature rose to 65°C. and the solution was stirred for 90 minutes at this temperature and20 ml of demineralized water were added when the reaction was finished.Excess pyrrolidine was distilled off under reduced pressure to obtain anoily phase and an aqueous phase. These are saturated with sodiumchloride at 20° C. and 1 ml of 32% sodium hydroxide was added.Extraction was done with ether and after drying and concentrating bydistilling under reduced pressure, the oil obtained was purified bychromatography over silica (eluent:ethyl acetate with 5% oftriethylamine) to obtain 8.31 g of[trans(±)]2,3-dihydro-1-(1-pyrrolidinyl)-1H-inden-2-ol.

STEP B:[Trans(±)]2,3-dihydro-N-methyl-2-(1-pyrrolidinyl)-1H-inden-1-amine

A mixture of 8.71 g of the product of Step A, 87 ml of methylenechloride and 13.8 ml of triethylamine was cooled to -20° C. and at thistemperature a solution of 6.6 ml of methane sulfonyl chloride and 8.7 mlof methylene chloride was added. The mixture was stirred for 20 minutesat -20° C. and then allowed to return to 0° C. and washed with icedwater. The wash water was extracted with methylene chloride and thecombined organic phases were dried and concentrated to dryness underreduced pressure to obtain 13.36 g of a resin corresponding to thetrans(±)methane sulfonate of2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-2-ol. The residue was treated inan autoclave with a 35 to 40% aqueous solution of monomethylamine byheating to 80° C. for 20 hours (pressure stabilized at 3 bars). It wasthen cooled to 20° C., and taken up in 100 ml of ether, saturated withsodium chloride and decanted. The organic phase was washed withsaturated salt water, then dried, treated with activated charcoal,filtered, rinsed and concentrated to dryness under reduced pressure toobtain 6.98 g of a resin which was purified by chromatography oversilica (eluent:ethyl acetate-methanol-triethylamine 85-10-5) to obtain3.71 g of[trans(±)]2,3-dihydro-N-methyl-2-(1-pyrrolidinyl)-1H-inden-1-amine.

STEP C:[Trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamide

A mixture of 2.66 g of 3,4-dichlorophenylacetic acid, 2.11 g ofcarbonyldiimidazole and 20 ml of tetrahydrofuran was stirred for 1 hourand then a solution of 2.16 g of the product of Step B in 5 ml oftetrahydrofuran was added slowly. The mixture was stirred for 3 hours 30minutes and then the tetrahydrofuran was distilled off under reducedpressure. The residue was taken up in 100 ml of ether and after washingwith a saturated solution of sodium bicarbonate, then with saturatedsalted water, drying and concentrating to dryness under reducedpressure, 4.68 g of[Trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamidein the form of a base were obtained.

Preparation of the Hydrochloride

The said product was dissolved at 50° C. in 10 ml of 99% ethanol, and tothe hot solution, 3 ml of an ethanol solution of anhydrous hydrochloricacid (titer=5.75N) were added. After filtering immediately hot, thefiltrate was rinsed with ethanol at 50° C. and crystallization wasinitiated at 30° C. The mixture stood for 2 hours at 20° C. forcrystallization to take place and the crystals were separated, rinsedwith ethanol and with ether, dried under reduced pressure to obtain3.815 g of the expected hydrochloride melting at 242° C.

EXAMPLE 2[Trans(±)]3,4-dichloro-N-[2,3-dihydro-1-(1-pyrrolidinyl)-1H-inden-2-yl]-N-methyl-benzene-acetamideand its fumarate STEP A:[Trans(±)]2,3-dihydro-1-[methyl(benzyl)-amino]-1H-inden-2-ol

A mixture of 10.06 g of 2,3-epoxy-indane, 50 ml of demineralized waterand 15 ml of N-methyl-benzylamine was stirred at 95° C. for 1 hour andafter cooling to 20° C., 50 g of ice were added. The gum obtained wasfiltered at 0° to +5° C., rinsed with water and re-dissolved in 250 mlof ethyl acetate. Extraction was done successively with 70 ml, 50 ml,and 30 ml of 2N hydrochloric acid and the aqueous phases were washedwith ethyl acetate. 150 ml of ethyl acetate were added to thehydrochloric extracts and the pH was adjusted to 9 to 10 by 25 g ofsodium bicarbonate with stirring and 0.5 ml of sodium hydroxide wereadded. The mixture was decanted, re-extracted with ethyl acetate, washedwith salted water, dried, treated with activated charcoal, rinsed, andconcentrated to dryness under reduced pressure to obtain 17.29 g ofresin which were taken up in 60 ml of n-hexane. Crystallization wasinitiated at 20° C. and after triturating, separating, rinsing withn-hexane and drying, 15.95 g of[Trans(±)]2,3-dihydro-1-[methyl(benzyl)-amino]-1H-inden-2-ol melting at64° C. were obtained.

STEP B:[Trans(±)]1-[2,3-dihydro-2-[methyl-(benzyl)-amino]-1H-inden-1-yl]-pyrrolidine

a) A solution of 13.95 g of the product of Step A, 98 ml of methylenechloride and 23 ml of triethylamine was cooled to -20° C. and a solutionof 8.5 ml of methanesulfonyl chloride and of methylene chloride wasintroduced with stirring for 30 minutes at -20° C. The temperature wasreturned to 0° C. over 5 minutes, and after washing with iced water,drying and concentrating to dryness under reduced pressure, 20.48 g ofan oil were obtained corresponding to the methane sulfonate of[trans(±)]2,3-dihydro-1-[methyl-(benzyl)-amino]-1H-inden-2-ol.

b) 20.48 g of the said product were stirred at 85° C. in 60 ml ofpyrrolidine and 60 ml of demineralized water and the emulsion wasstirred at 65° C. for 90 minutes. Then, the excess pyrrolidine wasdistilled off under reduced pressure and the residue was taken up in awater-ice mixture. The gum obtained was filtered, rinsed with water anddissolved in ether. The water was decanted and the ethereal solution wasdried and concentrated to dryness under reduced pressure to obtain 15.39g of[Trans(±)]1-[2,3-dihydro-2-[methyl-(benzyl)-amino]-1H-inden-1-yl]-pyrrolidine.

STEP C:[Trans(±)]1-[2,3-dihydro-2-(methylamino)-1H-inden-1-yl]-pyrrolidine

15.39 g of the product of Step B, 230 ml of methanol, 15.5 ml ofhydrochloric acid and 9.25 g of 10% palladium on activated charcoal weremixed together and then hydrogenated for 2 hours 30 minutes withstirring and 1800 mbars pressure of hydrogen. The catalyst and theactivated charcoal were filtered off and the filtrate was rinsed withmethanol, then concentrated under reduced pressure to obtain an oil.Ether was added with stirring, followed by alkalizination with 15 ml of32% sodium hydroxide while maintaining the temperature at 20° C. Then,after stirring, decanting, re-extracting the aqueous phase with ether,drying the organic phases and concentrating to dryness under reducedpressure, 9.85 g of[Trans(±)]1-[2,3-dihydro-2-(methylamino)-1H-inden-1-yl]-pyrrolidine wereobtained.

STEP D:[Trans(±)]3,4-dichloro-N-[2,3-dihydro-1-(pyrrolidinyl)-1H-inden-2-yl]-n-methyl-benzene-acetamide

A mixture of 2.66 g of 3,4-dichlorophenyl-acetic acid, 2.10 g ofcarbonyl-diimidazole and 25 ml of tetrahydrofuran was stirred for 1 hourat 20° to 25° C. and then 2.16 g of the product of Step C was added in10 ml of tetrahydrofuran with stirring for 3 hours 30 minutes at 20° to25° C. after which the tetrahydrofuran was distilled off under reducedpressure. The residue was taken up in ether, washed with a saturatedsolution of sodium bicarbonate and then with water saturated with sodiumchloride. After drying and concentrating to dryness under reducedpressure, 5.048 g of[Trans(±)]3,4-dichloro-N-[2,3-dihydro-1-(pyrrolidinyl)-1H-inden-2-yl]-n-methyl-benzene-acetamideas a fluid resin.

Preparation of the Fumarate

The crude base was dissolved in 50 ml of 99% ethanol, then filtered andrinsed with ethanol, 1.25 g of fumaric acid were added with heating todissolve it and the salt crystallized out on cooling and was separated,rinsed with 99% ethanol, then with ether, dried at 65° C. under reducedpressure to obtain 4.908 g of the fumarate which was crystallized firstfrom isopropanol with 5% of water, then from 99% ethanol for 4.038 g ofthe expected product melting at 140° C.

EXAMPLE 3[Trans(±)]3,4-dichloro-N-[2,2',3,3',5',6'-hexahydro-2-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-3-yl-N-methyl-benzene-acetamideand its hydrochloride STEP A:2,3,5,6-tetrahydro-spiro-pyran-4-(4H)-1'-indene

250 ml of tetrahydrofuran and 250 ml of hexamethylphosphorotriamide wereadded to 53 g of 50% sodium hydride in oil previously washed withpetroleum ether and then without exceeding 0° C., 58 g of indene in 50ml of tetrahydrofuran were added. The temperature was allowed to rise to15° C., and over 30 minutes at 16° C.±1°, 71.55 g of β-chloroethyl etherin 50 ml of tetrahydrofuran were added with stirring. Stirring wascontinued for another 90 minutes and then the mixture was carefullypoured into 1 liter of 2N hydrochloric acid containing about 500 g ofice. Extraction was done with isopropyl ether, and the extracts werewashed with water, dried, and stirred with animal charcoal and withalumina. After separating and concentrating to dryness under reducedpressure, 100 g of oil were obtained which was taken up in 200 ml ofpetroleum ether. Crystallization was initiated with icing for 3 hoursand then the crystals were separated, washed with iced petroleum etherto obtain 55 g of 2,3,5,6-tetrahydro-spiro pyran-4-(4H)-1'-indene. Themother liquor were evaporated to dryness and the residue was taken up in40 ml of methylene chloride, chromatographed on silica to obtain 25 g ofproduct which was crystallized from petroleum ether to obtain 14 g of2,3,5,6-tetrahydro-spiro-pyran-4-(4H)-1'-indene melting at 83° C.

STEP B: 2',3'-epoxy-2,3,5,6-tetrahydro-spiro-[pyran-4-(4H)-1'-indane]

At 15° C., 6.3 g of m-chloroperbenzoic acid were added to 5.58 g of theproduct of Step A in 60 ml of methylene chloride and the mixture wascooled slightly so as not to exceed 30° C. After half-an-hour, them-chlorobenzoic acid crystallized and the mixture stood for 1 hour.Then, it was poured into a mixture of water and sodium bicarbonate,extracted with methylene chloride, washed with a sodium bicarbonatesolution, dried and concentrated to dryness. The residue wascrystallized from methylene chloride and isopropyl ether. Afterseparating, washing with isopropyl ether and drying at 80° C., 4.23 g of2',3'-epoxy-2,3,5,6-tetrahydro-spiro-[pyran-4-(4H)-1'-indane] melting at157° C. were obtained.

STEP C:[Trans(±)]2,2',3,3',5',6'-hexanhydro-3-(1-pyrrolidinyl)-spiro-[1H-inden-1,4'-(4H)-pyran]-2-ol

11.66 g of the product of Step B in 10 ml of demineralized water and12.6 ml of pyrrolidine were heated to 60° to 70° C., then to 50° C.while stirring for 15 minutes, followed by cooling to 30° C., dilutingwith 100 ml of iced water, filtering, and rinsing the gum obtained withwater. The gum was taken up in ether and the water was decanted. Afterdrying and concentrating to dryness under reduced pressure, 12.8 g of[Trans(±)]2,2',3,3',5',6'-hexahydro-3-(1-pyrrolidinyl)-spiro-[1H-inden-1,4'-(4H)-pyran]-2-olwere obtained. The aqueous mother liquors were extracted with ether,dried, concentrated to dryness under reduced pressure, and 3.63 g of theexpected product were recovered.

Preparation of the Hydrochloride

The 16.43 g of product obtained were dissolved in 15 ml of ethanol andthen 11 ml of an ethanol solution of hydrochloric acid (5.75N) wereadded. The hydrochloride crystallized out and the suspension was dilutedslowly with stirring with 55 ml of ether, then separated, rinsed with anethanol-ether mixture, then with ether and dried under reduced pressureat 60° to 65° C. to obtain 13.65 g of the hydrochloride melting at 183°C.

STEP D: Methane sulfonate of[trans(±)]2,2',3,3',5',6'-hexahydro-3-(1-pyrrolidinyl)-spiro-[1H-inden-1,4'-(4H)-pyran]-2-ol

9.25 ml of triethylamine were introduced into a solution of 6.19 g ofthe product of Step C in 40 ml of methylene chloride which was cooled to-15° C. and a solution of 3.1 ml of methane sulfonyl chloride (0.04M) in20 ml of methylene chloride was added with stirring for 30 minutes at-15° C.±2°. The temperature was returned to 0° C. and the reactionmedium was poured into 100 ml of water at +10° C. After decanting,extracting with methylene chloride, washing with water, drying, addingsilica, stirring for 5 minutes, filtering, rinsing and concentrating todryness under reduced pressure, 7.45 g of an oil were obtained. The oilwas dissolved in 30 ml of ether at 20° C. and crystallization wasinitiated. The crystals were separated, rinsed with ether, and driedunder reduced pressure to obtain 5.15 g of methane sulfonate of[trans(±)]2,2',3,3',5',6'-hexahydro-3-(1-pyrrolidinyl)-spiro-[1H-inden-1,4'-(4H)-pyran]-2-olmelting at 136° to 137° C.

STEP E:[Trans(±)]2,2',3,3',5',6'-hexahydro-N-methyl-2-(1-pyrrolidinyl)-spiro-[1H-inden-1,4'-(4H)-pyran]-3-amine

A mixture of 4.65 g of the product of Step D and 9.3 ml of a 35 to 40%aqueous solution of methylamine was stirred at 70° C. for 18 hours 30minutes in an autoclave and the pressure stabilized at 1.2-1.4 bar.After cooling, the mixture was taken up in 20 ml of saturated salt waterand 100 ml of ether with stirring to dissolve the gum. Then the mixturewas decanted, extracted with ether, washed with salted water, dried andconcentrated to dryness under reduced pressure to obtain a thick oilwhich was dissolved in 10 ml of n-hexane at 40° C. Crystallization wasinitiated and the crystals were separated at 0°-+5° C., rinsed withn-hexane, dried under reduced pressure to obtain 3.26 g of[Trans(±)]2,2',3,3',5',6'-hexahydro-N-methyl-2-(1-pyrrolidinyl)spiro[1H-inden-1,4'-(4H)-pyran]-3-aminemelting at 88° C.

Preparation of the Dihydrochloride

2.18 g of the product were suspended in 7 ml of ethanol and 3.5 ml ofethanol containing anhydrous hydrochloric acid (5.75N) were added at 20°C. After filtering, 10 ml of ether were added slowly to the filtrate andthe crystals obtained were separated, rinsed with an ethanol-ethermixture and with ether, then dried under reduced pressure at 60° to 65°C. to obtain 2.74 g of the dihydrochloride melting at 270° C.

STEP F:[Trans(±)]3,4-dichloro-N-[2,2',3,3',5',6'-hexahydro-2-(1-pyrrolidinyl)spiro[1H-inden-1,4'-(4H)-pyran]-3-yl-N-methyl-benzene-acetamide

Using the procedure of Step C of Example 1, 789 mg of3,4-dichlorophenylacetic acid in 10 ml of tetrahydrofuran and 624 mg ofcarbonyldiimidazole and 1 g of the product (base) of Step E were reactedto obtain 1.443 g of[Trans(±)]3,4-dichloro-N-[2,2',3,3',5',6'-hexahydro-2-(1-pyrrolidinyl)spiro[1H-inden-1,4'-(4H)-pyran]3-yl-N-methyl-benzene-acetamidemelting at 131° C. after purification with n-hexane.

Preparation of the Hydrochloride

0.5 g of base were dissolved in 3 ml of ethanol at reflux and thesolution was filtered hot and rinsed with boiling ethanol. 0.4 ml of asolution in ethanol of anhydrous hydrochloric acid (5.75N) were added tothe filtrate and after separating, rinsing with 100% ethanol and withether and drying under reduced pressure at 60° to 65° C., 504 mg ofhydrochloride melting at 230° C. were obtained.

EXAMPLE 4 (E) butenedioate of[trans(±)]3,4-dichloro-N-[2,2',3,3',5',6'-hexahydro-3-(1-pyrrolidinyl)-spiro(1H-inden-1-,4'-(4H)-pyran]-2-yl]-N-methyl-benzene-acetamideSTEP A:[Trans(±)]2,2',3,3',5',6'-hexahydro-3-[methyl-(benzyl)-amino]spiro[1H-inden-1,4'-(4H)-pyran]-2-ol

Using the procedure of Step A of Example 2, 10.1 g of2,3'-epoxy-2,3,5,6-tetrahydrospiro-pyran-4-(4H)-1'-indane in 10 ml ofmethylbenzylamine and 50 ml of demineralized water was reacted to obtain12.79 g of[trans(±)]2,2',3,3',5',6'-hexahydro-3-[methyl-(benzyl)-amino]-spiro-(1H-inden-1,4'-(4H)-pyran]-2-olwhich was used as is for the following part of the synthesis.

Preparation of the Hydrochloride

4.40 g of the said base were dissolved in 15 ml of 100% ethanol at 20°C. and the solution was filtered. 4 ml of an ethanol solution ofanhydrous hydrochloric acid (5.75N) were added to it, followed bydilution with 24 ml of ether at 20° C. Crystallization was initiated at20° C. and 24 ml of ether were added. The crystals were separated at 20°C., rinsed with an ethanol-ether mixture, then with ether, dried underreduced pressure at 60° to 65° C. to obtain 4.2 g of the hydrochloridemelting at 192° C.

STEP B: Methane sulfonate of [trans(±)2,2',3,3',5',6'-hexahydro-3-[methyl(benzyl)-amino]spiro-[1H-inden-1,4'-(4H)-pyran]-2-ol

Using the procedure of Step B of Example 2, 12.79 g of the product ofStep A in 100 ml of methylene chloride, 16.5 ml of triethylamine, and6.1 ml of methane sulfonyl chloride in 30 ml of methylene chloride werereacted to obtain 16.07 g of methane sulfonate of [trans(±)2,2',3,3',5',6'-hexahydro-3-[methyl(benzyl)-amino]-spiro[1H-inden-1,4'-(4H)-pyran]-2-ol.

STEP C:[Trans(±)]2,2',3,3',5',6'-hexahydro-N-methyl-N-(benzyl)-3-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-2-amine

Using the procedure of b) of Step B of Example 2, the 16.07 g of theproduct of Step B, 37 ml of pyrrolidine and 37 ml of demineralized waterwere reacted to obtain 14.16 g of[Trans(±)]2,2',3,3',5',6'-hexahydro-N-methyl-N-(benzyl)-3-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-2-aminewhich was used as is for the remainder of the synthesis.

Preparation of the Hydrochloride

2.60 g of said base were dissolved with warming in 6.5 ml of isopropanoland at 20° C. 4 ml of anhydrous (4.4N) hydrochloric acid in isopropanolwere added. After filtering and rinsing with isopropanol, 42 ml of etherwere added to the filtrate. The gum was separated, rinsed with ether,dried under reduced pressure at 62° to 65° C. to obtain 2.82 g of thehydrochloride melting at 150° C.

STEP D: Dihydrochloride of[trans(±)]2,2',3,3',5',6'-hexahydro-N-methyl-3-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-2-amine

Using the procedure of Step C of Example 2, 12.35 g of crude base ofStep C, 247 ml of methanol and 17.3 ml of hydrochloric acid and 7.4 g of10% palladium on activated charcoal were subjected to hydrogenation at24° to 26° C. under 1800 mbars for about 1 hour. At the end of thereaction, the activated charcoal and the catalyst were filtered offunder nitrogen, followed by rinsing with methanol and concentrating thefiltrate under reduced pressure. The residue was dissolved at 20° C. in60 ml of isopropanol, and after initiating crystallization at 20° C.,the solution stood at ambient temperature for 2 hours. The crystals wereseparated, rinsed with isopropanol, then with ether and dried underreduced pressure at 65° C. to obtain 8.80 g of crude product. 5.48 g ofthe said product were dissolved in 20 ml of methanol, filtered, rinsedwith methanol, concentrated under reduced pressure, taken up inisopropanol and dissolved by warming. After filtering hot, and rinsingwith boiling isopropanol, crystallization was initiated and the crystalswere separated, rinsed with isopropanol and with ether and dried underreduced pressure to obtain 5.16 g of the anhydrous dihydrochloride of[trans(±)]2,2',3,3',5',6'-hexahydro-N-methyl-3-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-2-aminein the form of the dihydrochloride melting at 235° C. of the hydratedhydrochloride.

STEP E: (E) butenedioate of[trans(±)]3,4-dichloro-N-[2,2',3,3',5',6'-hexahydro-3-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-2-yl]-N-methyl-benzene-acetamide

Using the procedure of Step D of Example 2, 2.05 g of3,4-dichlorophenylacetic acid, 20 ml of tetrahydrofuran, 1.62 g ofcarbonyldiimidazole, 2.6 ml of triethylamine and 3.27 g of the productof Step D were reacted to obtain 4.61 g of (E) butenedioate of [trans(±)3,4-dichloro-N-[2,2',3,3',5',6'-hexahydro-3-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-2-yl]-N-methyl-benzene-acetamide.4.456 g of the product were purified by chromatography on silica(eluent:methylene chloride-ethyl acetate 1-1). The solvent waseliminated to obtain 3.71 g of pure product.

Obtaining the Fumarate

3.474 g of the purified base were dissolved in 15 ml of ethanol and 941mg of fumaric acid were added with heating to obtain a solution. Thesolution was filtered hot and rinsed with boiling ethanol. The filtratecrystallized hot and the crystals were separated at 20° C. rinsed withethanol and with ether and dried under reduced pressure at 60° to 65° C.to obtain 3.631 g of the fumarate melting at 152° C.

Using the procedure of Step C of Example 1, the[trans(±)]2,3-dihydro-N-methyl-2-(1-pyrrolidinyl)-1H-inden-1-amine ofStep B of Example 1 and the corresponding acid were reacted to obtainthe products of Example 5 to 14.

EXAMPLE 5[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-(trifluoromethyl)-benzene-acetamideand its hydrochloride

By using 0.645 g of the product of Step B of Example 1 and 0.796 g of4-trifluoromethylphenyl acetic acid, 0.673 g of the expectedhydrochloride melting at 245° C. were obtain.

Analysis: C₂₃ H₂₅ F₃ N₂ O, HCl: 438.923.

    __________________________________________________________________________    Calculated:                                                                         % C 62.94                                                                            % H                                                                              5.97                                                                             % N 6.38                                                                             % F                                                                              12.99                                                                            % Cl 8.08                                     Found:    62.7  6.2    6.1   12.9    7.2                                      __________________________________________________________________________

EXAMPLE 6[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-3-(trifluoromethyl)-benzene-acetamideand its hydrochloride

By using 0.432 g of the product of Step B of Example 1 and 0.530 g ofm-trifluoromethylphenyl acetic acid, 0.786 g of[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-3-(trifluoromethyl)-benzene-acetamide,then 0.606 g of the expected hydrochloride melting at about 211° C.(decompose) were obtained.

Analysis: C₂₃ H₂₅ F₃ N₂ O, HCl: 438.923.

    __________________________________________________________________________    Calculated:                                                                         % C 62.94                                                                            % H                                                                              5.97                                                                             % N 6.38                                                                             % F                                                                              12.99                                                                            % Cl 8.08                                     Found:    62.8  6.1    6.3   13.0    8.2                                      __________________________________________________________________________

EXAMPLE 7[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-2-(trifluoromethyl)-benzene-acetamideand its hydrochloride

By using 0.432 g of the products of Step B of Example 1 and 0.530 g of0-trifluoromethylphenyl acetic acid, 0.945 g of[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-2-(trifluoromethyl)-benzene-acetamideand its hydrochloride, then 0.751 g of the expected hydrochloridemelting at about 260° C. (decompses) were obtained.

Analysis: C₂₃ H₂₅ F₃ N₂ O, HCl: 438.923.

    __________________________________________________________________________    Calculated:                                                                         % C 62.94                                                                            % H                                                                              5.97                                                                             % N 6.38                                                                             % F                                                                              12.99                                                                            % Cl 8.08                                     Found:    62.6  6.0    6.1   13.3    8.4                                      __________________________________________________________________________

EXAMPLE 8[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-nitro-benzene-acetamideand its hydrochloride

By using 1.73 g of the product of Step B of Example 1 and 1.88 g ofp-nitrophenyl acetic acid, 3.7 g of[trans(±)]N-2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-nitro-benzene-acetamideand------------then 0.33 g of the expected hydrochloride melting at 236°C. were obtained.

Analysis: C₂₂ H₂₅ N₃ O₃, HCl: 415.923.

    ______________________________________                                        Calculated:                                                                           % C    63.53  % H  6.30 % N  10.10                                                                              % Cl  8.53                          Found:         63.4        6.2       9.9        8.6                           ______________________________________                                    

EXAMPLE 9[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-3-nitro-benzene-acetamideand its hydrochloride

By using 0.432 g of the product of Step B of Example 1 and 0.471 g ofm-nitrophenyl acetic acid, 0.838 g of[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-3-nitro-benzene-acetamide------------then0.58 g of the expected hydrochloride melting at about 160° C. wereobtained.

Analysis: C₂₂ H₂₅ N₃ O₃, HCl: 415.923.

    ______________________________________                                        Calculated:                                                                           % C    63.53  % H  6.30 % N  10.10                                                                              % Cl  8.53                          Found:         63.6        6.4       10.1       8.5                           ______________________________________                                    

EXAMPLE 10[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-2-nitro-benzene-acetamideand its hydrochloride

By using 0.432 g of the product of Step B of Example 1 and 0.471 g ofo-nitrophenyl acetic acid, 0.492 g of[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-2-nitro-benzene-acetamidehydrochloride melting at about 215° C. were obtained.

Analysis: C₂₂ H₂₅ N₃ O₃, HCl: 415.923.

    ______________________________________                                        Calculated:                                                                           % C    63.53  % H  6.30 % N  10.10                                                                              % Cl  8.53                          Found:         63.6        6.4       10.1       8.5                           ______________________________________                                    

EXAMPLE 11[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-3,4,5-trimethoxy-benzene-acetamideand its hydrochloride

By using 0.432 g of the product of Step B of Example 1 and 0.588 g of3,4,5-trimethoxyphenyl acetic acid, 1.070 g of[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-3,4,5,-trimethoxy-benzene-acetamideand then 0.789 g of its hydrochloride melting at 217° C. were obtained.

Analysis: C₂₅ H₃₂ H₂ N₄ O, HCl: 461.006.

    ______________________________________                                        Calculated:                                                                           % C    65.13  % H  7.21 % N  16.08                                                                              % Cl  7.69                          Found:         65.0        7.3       15.9       7.4                           ______________________________________                                    

EXAMPLE 12[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-4-N-dimethyl-benzene-acetamideand its hydrochloride

By using 0.650 g of the product of Step B of Example 1 and 0.586 g ofpara-tolyl acetic acid, 1.10 g of[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-4-N-dimethyl-benzene-acetamideand then 0.665 g of its hydrochloride melting at 212° C. were obtained.

Analysis: C₂₃ H₂₈ N₂ O, HCl: 384.948.

    ______________________________________                                        Calculated:                                                                           % C    71.76  % H  7.50 % N  7.28 % C   9.21                          Found:         71.8        7.6       7.1        9.2                           ______________________________________                                    

EXAMPLE 13[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-3,4-dimethoxy-N-methyl-benzene-acetamideand its fumarate

By using 0.650 g of the product of Step B of Example 1 and 0.765 g of3,4-dimethoxyphenyl acetic acid, 1.14 g of[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-3,4-dimethoxy-N-methyl-benzene-acetamide------------wereobtained. To 1 g of this product, there was added 0.35 g of fumaric acidin 7 ml of ethanol, and after filtering, 0.886 g of the expected saltmelting at 186° C. were obtained.

Analysis: C₂₄ H₃₀ N₂ O₃ C₄ H₄ O₄ : 510.583.

    ______________________________________                                        Calculated:                                                                              % C    65.87    % H  6.71  % N  5.49                               Found:            66.1          6.4        5.3                                ______________________________________                                    

EXAMPLE 14[trans(±)]2-(3,4-dichlorophenoxy)-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-acetamideand its hydrochloride

By using 0.432 g of the product of Step B of Example 1 and 0.575 g of3,4-dichlorophenoxy acetic acid, 0.790 g of[trans(±)]2-(3,4-dichlorophenoxy)-N-(2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-acetamide------------andthen 0.687 g of the hydrochloride melting at 196° C. were obtained.

Analysis: C₂₂ H₂₄ N₂ O₂, HCl: 455.815.

    ______________________________________                                        Calculated:                                                                           % C    57.07  % H  5.53 % N  6.14 % Cl  23.33                         Found:         58.0        5.5       6.2        23.0                          ______________________________________                                    

EXAMPLE 15[Trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-benzamideand its hydrochloride

0.670 g of 3,4-dichlorobenzoic acid in ether were added to 0.650 g ofthe product of Step A of Example 1 in ether with stirring for 16 hoursat ambient temperature. Then the mixture was poured into iced water andthe ethereal phase was separated by decanting, washed with a saturatedaqueous solution of sodium bicarbonate and then with salted water,extracted with ether, dried, and the solvents were elminated underreduced pressure to obtain 1.2 g of the expected product in the form ofthe base. 1.1 g of the base were dissolved in 25 ml of ethanol and 0.8ml of an ethanol solution of hydrogen chloride (5.75N) were added toobtain 1.05 g of the hydrochloride.

Analysis: C₂₁ H₂₂ Cl₂ N₂ O, HCl: 425.789.

    ______________________________________                                        Calculated:                                                                           % C    59.24  % H  5.44 % N  6.58 % Cl  24.98                         Found:         59.0        5.5       6.6        24.7                          ______________________________________                                    

EXAMPLE 16[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-nitro-benzene-acetamide(isomer A) and its hydrochloride STEP A: Resolution oftrans(±)2,3-dihydro-N-methyl-2-(1-pyrrolidinyl)-1H-inden-1-amine IsomerA

12.1 g of D (+) di-p-tolyl tartaric acid in solution in 22.5 ml ofmethanol were added to a solution of 6.48 g of the product of Step B ofExample 1 in 7.5 ml of methanol, and the mixture was kept in contact for4 hours at +4° C. After separating, 5.293 g of isomer A salt werecollected after crystallizing again from methanol. The melting point wasabout 170° to 178° C. and the specific rotation was [α]_(D) ²⁰=+97.5°±5° (c=0.26% H₂).

The isomer A salt was taken up in 40 ml of sodium hydroxide and theaqueous phase was separated by decanting and then saturated with sodiumchloride and extracted with ether. The ether phase was then dried andthe solvent was eliminated under reduced pressure to obtain 1.852 g ofisomer A in the base form melting at <50° C. and having a specificrotation of [α]_(D) ²⁰ =-10.5°±1° (c=1% in CH₃ OH).

Isomer B

The methanol collected after filtering the above isomer A salt wasconcentrated to dryness and the residue was taken up in water, ether andsodium hydroxide as above and after extracting with ether andelimination of the solvent, 4.1 g of base were obtained which wasdissolved in 6 ml of methanol. A solution of 7.68 g of L(-) di-p-tolyltartaric acid in 20 ml of methanol was added and crystallization wasinitiated. The solution stood for 4 hours and after separating andcrystallizing from methanol, 3.208 g of the isomer B salt melting atabout 117° C. and having a specific rotation of [α]_(D) ²⁰ =-19.5°±2°(c=0.5% DMF) were obtained.

The isomer B salt was taken up in water and ether and sodium hydroxidewas added as above. After extraction with ether and elimination of thesolvent under reduced pressure, 1.117 g of isomer B were obtained in theform of a base melting at >50° C. and having a specific rotation of[α]_(D) ²⁰ =+10.5°±1.5° (c=1% CH₃ OH).

STEP B

Using the procedure of Step C of Example 1, 0.649 g of isomer A in theform of the base of Step A and 0.707 g of p-nitrophenyl acetic acid werereacted to obtain 1.361 g of the expected product in the form of thebase, then 0.957 g of the hydrochloride melting about 238° C. and havinga specific rotation of [α]_(D) ²⁰ =+85°±1.5° (c=1% H₂ O)

Analysis: C₂₂ H₂₅ N₃ O₃, HCl: 415.923.

    ______________________________________                                        Calculated:                                                                           % C    63.53  % H  6.30 % N  10.10                                                                              % Cl  8.53                          Found:         63.4        6.3       10.1       8.5                           ______________________________________                                    

EXAMPLE 17N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-nitro-benzene-acetamide(isomer B) and its hydrochloride

Using the procedure of Step C of Example 1, 0.649 g of isomer B in theform of the base of Step A of Example 16 and 0.707 g of p-nitrophenolacetic acid were reacted to obtain 1.369 g ofN-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-4-nitro-benzene-acetamide(isomer B) and its hydrochloride in the form of the base, then 0.982 gof hydrochloride melting at about 238° C. and having a specific rotationof [α]_(D) ²⁰ =-80°±1.5° (c=1% H₂ O).

Analysis: C₂₂ H₂₅ N₃ O₃ HCl: 415.923.

    ______________________________________                                        Calculated:                                                                           % C    63.53  % H  6.30 % N  10.10                                                                              % Cl  8.53                          Found:         63.5        6.3       10.2       8.7                           ______________________________________                                    

EXAMPLE 18[Trans(±)]-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-2,4-dinitro-N-methyl-benzene-acetamideand its hydrochloride STEP A: Oxalate of[trans(±)]2,3-dihydro-N-methyl-2-(1-pyrrolidinyl)-1H-inden-1-amine

1.94 g of the product of Step B of Example 1 were dissolved in 2 ml ofethanol and 1.35 g of dihydrated oxalic acid were added at 50° C. Aftercooling, separating and rinsing with ethanol, then with ether, 2.3 g ofcrude product were obtained which was crystallized from methanol with 5%of water to obtain oxalate of[trans(±)]2,3-dihydro-N-methyl-2-(1-pyrrolidinyl)-1H-inden-1-aminemelting at 215° C.

Analysis:

    ______________________________________                                        Calculated:                                                                              % C    58.11    % H  6.60  % N  7.97                               Found:            58.0          6.7        7.7                                ______________________________________                                    

STEP B:[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-2,4-dinitro-N-methyl-benzene-acetamideand its hydrochloride

Using the procedure of Step C of Example 1, 0.703 g of the oxalate ofStep A and 0.588 g of 2,4-dinitrophenyl acetic acid were reacted toobtain 0.81 g of crude product which was chromatographed over silica(eluent:ethyl acetate, then ethyl acetate with 5% of triethylamine) toobtain 0.359 g of[trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-2,4-dinitro-N-methyl-benzene-acetamidein base form, then 0.332 g of the hydrochloride melting at 260° C.(decomposes).

Analysis: C₂₂ H₂₄ N₄ O₅ HCl: 460.92.

    ______________________________________                                        Calculated:                                                                           % C    57.32  % H  5.47 % N  12.16                                                                              % Cl  7.69                          Found:         57.4        5.5       12.0       8.0                           ______________________________________                                    

EXAMPLE 19[Trans(±)]3,5-bis-(trifluoromethyl)-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]N-methyl-benzene-acetamideand its hydrochloride

Using the procedure of Step C of Example 1, 0.432 g of the product ofStep B of Example 1 and 3,5-bis-trifluoromethyl-phenyl acetic acid werereacted to obtain the expected hydrochloride (yield of 68%) melting atabout 226° C. (decomposes).

Analysis:

    __________________________________________________________________________    Calculated:                                                                         % C 58.86                                                                            % H                                                                              4.97                                                                             % N 5.52                                                                             % F                                                                              22.49                                                                            % Cl 6.99                                     Found:    57.0  5.0    5.5   22.8    7.2                                      __________________________________________________________________________

EXAMPLE 20[Trans(±)]N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-3,4,5-trimethoxy-benzamideand its hydrochloride

At ambient temperature, 1 g of the oxalate of Step A of Example 18 and0.9 ml of triethylamine were mixed together in tetrahydrofuran and 0.515g of 3,4,5-trimethoxy-benzoic acid in 5 ml of tetrahydrofuran wereadded. The mixture was stirred for 16 hours and then poured into 30 mlof iced water and decanted. The organic phase was washed with an aqueoussolution of sodium bicarbonate, then with salted water and extractedwith ether. The extracts were dried and the solvents were eliminatedunder reduced pressure to obtain 0.457 g of the expected product in thebase form melting at 174° C. The latter was dissolved in 1 ml of anethanol solution of hydrogen chloride (about 1.68N) and the solventswere eliminated under reduced pressure. The residue was taken up in 5 mlof ether and crystallization was initiated. The expected hydrochloridewas separated and dried at 80° C. under reduced pressure and melted atabout 210° C.

Analysis: C₂₄ H₃₀ N₂ O₄ : 446.979.

    ______________________________________                                        Calculated:                                                                           % C    64.49  % H  6.99 % N  6.27 % Cl  7.93                          Found          64.7        7.0       6.2        8.2                           ______________________________________                                    

EXAMPLE 21[Trans(±)]3-(aminosulfonyl)-4-chloro-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methylbenzamide and its hydrochloride

Using the procedure of Example 20, 0.907 g of the product of Step B ofExample 1 and with 4-chloro-3-amino-sulfonyl benzoic acid chloride werereacted to obtain the expected hydrochloride (yield of 66%) meltingat >260° C.

Analysis:

    __________________________________________________________________________    Calculated:                                                                         % C 53.62                                                                            % H                                                                              5.35                                                                             % N 8.93                                                                             % S                                                                              6.82                                                                             % Cl 15.07                                    Found:    53.4  5.6    8.6   6.7     14.8                                     __________________________________________________________________________

The 4-chloro-3-aminosulfonyl benzoic acid chloride used at the start ofthe Example was prepared as follows:

1 g of 3-sulfonyl-4-chloro benzoic acid were heated at reflux withstirring for 2 hours and excess thionyl chloride was eliminated underreduced pressure to obtain 1.098 g of the expected product melting at158° C.

EXAMPLE 22[Trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-α-dimethyl-benzene-acetamideisomer A and isomer B and their hydrochloride

A mixture of 2.30 g of α-methyl-3,4-dichlorophenyl acetic acid, 1.73 gof the product of Step B of Example 1, 0.08 g of4-dimethylamino-pyridine and 2.55 g of dicyclohexylcarbodiimide wasstirred for 5 hours at ambient temperature in methylene chloride and theurea formed was filtered off. The filtrate was concentrated to drynessunder reduced pressure and the residue was taken up in ether, washedwith a saturated aqueous solution of sodium bicarbonate, then withsalted water, re-extracted with ether, dried and the solvents wereeliminated under reduced pressure to obtain 4 g of crude product in theform of the base which was chromatographed over silica (eluent:ethylacetate-triethylamine 98-2) to obtain 1.05 g of isomer A and 1.0 g ofisomer B.

Isomer A: Preparation of the Hydrochloride

0.6 ml of an ethanol solution of hydrogen chloride (5.75N) were added to0.90 g of isomer A in the form of the base in 8 ml of ethanol to obtain0.7 g of the hydrochloride after crystallization in isopropanol. Itmelted at 174° C.

Analysis: C₂₃ H₂₆ Cl₂ N₂ O, HCl: 453.839.

    ______________________________________                                        Calcu-                                                                              % C 53.62 % H 5.35 % N 8.93                                                                             % S 6.82                                                                             % Cl 15.07                             lated:                                                                        Found:                                                                              53.4      5.6      8.6    6.7    14.8                                   ______________________________________                                    

Isomer B: Preparation of the Hydrochloride

The operation for isomer A was repeated with 0.90 g of isomer B in theform of the base to obtain 0.55 g of hydrochloride melting at 176° C.

EXAMPLE 23[Trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(1-piperidinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamideand its hydrochloride STEP A:[Trans(±)]2,3-dihydro-1-piperidinyl-1H-inden-2-ol

At 50° C. and over 5 minutes, 50 ml of piperidine and 50 ml of waterwere added to 21.25 g of 2,3-epoxy-indane and the mixture was maintainedfor 2 hours with stirring at this temperature. The solution was thencooled to 20° C. and was saturated with sodium chloride. 5 ml of sodiumhydroxide were added, followed by extraction with ether. The extractswere concentrated to dryness under reduced pressure and the residue wastaken up in 200 ml of ethyl acetate at 40° C., filtered, dried, and thesolvents were eliminated under reduced pressure. The residue was takenup in isopropyl ether, filtered and taken to dryness to obtain 26.82 gof crude product which was purified by chromatography over silica,(eluent: ethyl acetate with 1% of triethylamine) to obtain[trans(±)]2,3-dihydro-1-piperidinyl-1H-inden-2-ol melting at about 82°C.

STEP B: [Trans(±)]2,3-dihydro-N-methyl-2-piperidinyl-1H-inden-1-amine

A solution of 4.34 g of the product of Step A and 3.7 ml oftriethylamine in 30 ml of tetrahydrofuran was cooled to -20° C. and thenover 7 minutes, 1.9 ml of methane sulfonyl chloride in 4 ml oftetrahydrofuran were added. Stirring was maintained for 15 minutes andthen the temperature was allowed to return to 0° C. 17 ml of methylaminein 33% ethanol solution were added with stirring while allowing thetemperature of the reaction mixture to return to ambient. After stirringfor 25 hours, the solvent was eliminated under reduced pressure and theresidue was taken up in 10 ml of salted water. 5 ml of sodium hydroxidewere added and extraction was done with ethyl acetate. The extracts wereconcentrated to dryness to obtain 4.743 g of crude product which wasdissolved in 23 ml of an ethanol solution of hydrogen chloride (1.68N).Crystallization was initiated and the crystals were separated, dried at70° C. to obtain 9.12 g of[Trans(±)]2,3-dihydro-N-methyl-2-piperidinyl-1H-inden-1-amine meltingat >260° C.

Analysis:

    ______________________________________                                        Calculated:                                                                           % C 59.42  % H 7.98  % N 9.24                                                                              % Cl 23.38                               Found:  59.3       8.0       9.2     22.8                                     ______________________________________                                    

STEP C:[Trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(1-piperidinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamideand its hydrochloride

0.533 g of 3,4-dichlorophenyl acetic acid and 0.422 g ofcarbonyldiimidazole were stirred for 1 hour in 5 ml of tetrahydrofuranand 0.6 ml of triethylamine and then 0.606 g of the product of Step Bwere added. The mixture was stirred for 16 hours and the solvent waseliminated under reduced pressure. The residue was taken up in 30 ml ofethyl acetate and was washed with a saturated aqueous solution of sodiumbicarbonate, then with a saturated solution of sodium chloride. Afterdrying and concentrating to dryness under reduced pressure, 0.981 g ofcrude product were obtained.

Preparation of Hydrochloride

The said base was dissolved in 5 ml of ethanol and 1.5 ml of a 1.68Nsolution of hydrogen chloride in ethanol were added. Crystallization wasinitiated and the crystals were separated, rinsed with ethanol then withether, dried at 80° C. under reduced pressure to obtain 0.656 g of thehydrochloride melting at about 217° C.

Analysis:

    ______________________________________                                        Calculated:                                                                           % C 60.87  % H 6.00  % N 6.17                                                                              % Cl 23.43                               Found:  60.7       6.0       6.0     23.3                                     ______________________________________                                    

EXAMPLE 24[Trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(4-methyl-1-piperazinyl-1H-inden-1-yl]-N-methyl-benzene-acetamideSTEP A: [Trans(±)]2,3-dihydro-1-(4-methyl-1-piperazinyl)-1H-inden-2-ol

Using the procedure of Example 23, Step A, 14.57 g of 2,3-epoxy-indaneand 12.4 ml of N-methyl piperazine were reacted to obtain 6.447 g of[trans(±)]2,3-dihydro-1-(4-methyl-1-piperazinyl)-1H-inden-2-ol meltingat 132° C.

STEP B:[Trans(±)]2,3-dihydro-N-methyl-2-(4-methyl-1-piperazinyl)-1H-inden-1-amineand its hydrochoride

Using the procedure of Example 23, Step B, 4.64 g of the product of StepA were reacted to obtain 5.58 g of the expected product in the form ofthe base, then 6.79 g of hydrochloride melting at >260° C.

Analysis:

    ______________________________________                                        Calculated:                                                                           % C 50.79  % H 7.39  % N 11.84                                                                             % Cl 29.98                               Found:  51.3       7.4       11.8    28.5                                     ______________________________________                                    

STEP C:[Trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(4-methyl-1-piperazinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamide

Using the procedure of Example 23 Step C, 0.720 g of the hydrochlorideof Step B and 0.533 g of 3,4-dichlorophenyl acetic acid were reacted toobtain 1.070 g of[trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(4-methyl-1-piperazinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamidein the form of the base, then 0.866 g of its hydrochloride melting at223° C.

Analysis: C₂₃ H₂₇ Cl₂ N₃ O, 2HCl: 505.318

    ______________________________________                                        Calculated:                                                                           % C 54.67  % H 5.78  % N 8.31                                                                              % Cl 28.06                               Found:  54.5       5.9       8.2     27.5                                     ______________________________________                                    

EXAMPLE 25[Trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(dimethylamino)-1H-inden-1-yl]-N-methyl-benzene-acetamideand its hydrochloride STEP A:[Trans(±)]2,3-dihydro-1-(dimethylamino)-1H-inden-2-ol and itshydrochloride

Using the procedure of Step A of Example 23, but after the extractionwith ether and the elimination of the solvents under reduced pressure,the residue was taken up in ether and 70 ml of a 1.68N solution ofhydrogen chloride in ethanol were added. Crystallization was initiatedand after standing for 2 hours, the crystals were separated and rinsedwith ethanol and then with ether to obtain 15.15 g of[trans(±)]2,3-dihydro-1-(dimethylamino)-1H-inden-2-ol and itshydrochloride which after crystallization from isopropanol melted at184° C.

STEP B:[Trans(±)]2,3-dihydro-N-methyl-2-(dimethylamino)-1H-inden-1-amine andits oxalate

Using the procedure of Step B of Example 23, 4.27 g of the hydrochlorideof Step A were reacted to obtain 3.87 g of the expected product in theform of the base.

Formation of the Oxalate

3.82 g of the base were dissolved in 2 ml of ethanol and 2.67 g ofoxalic acid were added hot, and after rinsing with ethanol and then withether, 3.22 g of the oxalate melting at 170° C. were obtained.

Analysis:

    ______________________________________                                        Calculated:                                                                             % C 55.37    % H 6.50 % N 8.61                                      Found:    55.2         6.5      8.7                                           ______________________________________                                    

STEP C:[Trans(±)]3,4-dichloro-N-[2,3-dihydro-2-(dimethylamino)-1H-inden-1-yl]-N-methyl-benzene-acetamideand its hydrochloride

Using the procedure of Step C of Example 23, 0.650 g of the oxalate ofStep B above and 0.533 g of 3,4-dichlorophenylacetic acid were reactedto obtain 0.834 g of the expected product in the form of the base, then0.683 g of hydrochloride melting at about 233° C. (decomposes).

Analysis: C₂₀ H₂₂ Cl₂ N₂ O, HCl: 413.777.

    ______________________________________                                        Calculated:                                                                           % C 58.06  % H 5.60  % N 6.77                                                                              % Cl 25.70                               Found:  58.2       5.6       6.7     25.9                                     ______________________________________                                    

EXAMPLE 26[Trans(±)]3,4-dichloro-N-[2,3-dihydro-1,1-dimethyl-2-(1-pyrrolidinyl)-1H-inden-3-yl]-N-methyl-benzene-acetamideand its trans butene dioate STEP A: Dimethyl-1,1-indene oxide

A mixture of 1,1-dimethyl indene [prepared as in Boschond et al,Canadian J. of Chem., Vol. 42, p. 1718 (1964)] in 40 ml of methylenechloride, 75 ml of a 10% aqueous solution of sodium bicarbonate and 5.45g of sodium bicarbonate was cooled to 7° C. and 11.57 g ofmetachloroperbenzoic acid were added while maintaining the temperatureat less than 10° C. Then the mixture was stirred for 22 hours at ambienttemperature, filtered, decanted, and the aqueous phase was washed withmethylene chloride. The combined organic phases were washed with a 10%aqueous solution of sodium thiosulfate, then with a 10% aqueous solutionof sodium bicarbonate and then with water. After drying and eliminatingthe solvents under reduced pressure, 9.2 g of dimethyl-1,1-indene oxidewere obtained which was utilized as is in the following step.

STEP B: [Trans(±)]1,1-dimethyl-3-pyrrolidine-2-indanol

A mixture of 7 ml of pyrrolidine and 7 ml of water was added to 9 g ofthe product of Step A and the reaction medium was heated to 65° C. for 2hours. After cooling, diluting with 10 ml of water and eliminating theexcess of pyrrolidine under reduced pressure, extraction was done withethyl acetate. The extracts were dried and concentrated to dryness underreduced pressure to obtain 10 g of crude product which was purified bychromatography over silica (eluent:n-hexane-ethyl acetate-triethylamine(27-70-3) to obtain [trans(±)]1,1-dimethyl-3-pyrrolidine-2-indanolmelting at 86° C.

STEP C: Mesylate of [trans(±)]1,1-dimethyl-3-pyrrolidine-2-indanol

4.8 g of the product of Step B, 50 ml of tetrahydrofuran and 3.86 ml oftriethylamine were cooled to -20° C. and 1.8 g of methane sulfonylchloride in solution in 5 ml of tetrahydrofuran were added dropwise. Thetemperature was allowed to return to ambient and the reaction medium wasstirred for 64 hours. It was then diluted with iced water and 2 ml of0.1N sodium hydroxide were added. Extraction was done with ethyl acetateand the organic phase was washed with salted water, dried, and thesolvents were eliminated under reduced pressure to obtain 6.9 g ofmesylate of [trans(±)]1,1-dimethyl-3-pyrrolidine-2-indanol which wasused as is for the following step.

STEP D:[Trans(±)]2,3-dihydro-N-methyl-2-(1-pyrrolidinyl)-3,3-dimethyl-1H-inden-1-amine

A mixture of 6.9 g of the product of Step C in 15 ml of a 35 to 40%aqueous solution of methylamine was heated for 18 hours at 70° C. in anautoclave (P=1.5 bar) and after cooling and diluting with water,extraction was done with ethyl acetate. The organic phase was washedwith water, dried and concentrated under reduced pressure to obtain 6 gof crude[trans(±)]2,3-dihydro-N-methyl-2-(1-pyrrolidinyl)-3,3-dimethyl-1H-inden-1-aminewhich was purified by chromatography on silica (eluent:ethylacetate-n-hexane-triethylamine, 60-37-3).

STEP E:[Trans(±)]3,4-dichloro-N-[2,3-dihydro-1,1-dimethyl-2-(1-pyrrolidinyl)-1H-inden-3-yl]-N-methyl-benzene-acetamideand its trans butene dioate

Using the procedure of Step D of Example 2, 0.570 g of the product ofStep C and 0.668 g of 3,4-dichlorophenylacetic acid were reacted toobtain 1.232 g of the expected product in the form of its base. 1.064 gof this base were converted into the fumarate melting at 170° C.

Analysis: C₂₄ H₂₈ Cl₂ N₂ O, C₄ H₄ O₄ : 547.483.

    ______________________________________                                        Calculated:                                                                           % C 61.43  % H 5.89  % N 5.12                                                                              % Cl 12.95                               Found:  61.3       6.0       5.1     12.9                                     ______________________________________                                    

EXAMPLE 27[Trans(±)]N-[2,3-dihydro-1,1-dimethyl-2-(1-pyrrolidinyl)-1H-inden-3-yl]-N-methyl-4-nitrobenzene-acetamideand its trans butene dioate

Using the procedure of Step D of Example 2, 0.489 g of[trans(±)]2,3-dihydro-N-methyl-2-(1-pyrrolidinyl)-3,3-dimethyl-1H-inden-1-amineof Step D of Example 26 and 0.471 g of p-nitrophenyl acetic acid werereacted to obtain 0.888 g of the expected product in the form of itsbase, then 0.433 g of fumarate melting at 161° C.

Analysis: C₂₄ H₂₉ N₃ O₃. 1.25 C₄ H₄ O₄ : 552.602.

    ______________________________________                                        Calculated:                                                                             % C 63.03    % H 6.20 % N 7.60                                      Found:    62.8         6.3      7.5                                           ______________________________________                                    

EXAMPLE 28[Trans(±)]N-[2,3-dihydro-1,1-dimethyl-3-(1-pyrrolidinyl)-1H-inden-2-yl]-N-methyl-4-nitrobenzene-acetamideand its hydrochloride STEP A:[Trans(±)]2,3-dihydro-1[methyl(benzyl)-amino]-3,3-dimethyl-1H-inden-2-o

10.4 ml of N-benzylmethylamine in 50 ml of water were mixed with 12.4 gof 1,1-dimethyl indene oxide of Step A of Example 26 and the mixture washeated for 3 hours at 90° to 95° C. After cooling to 5° C., the aqueousphase was decanted off and the organic phase was taken up with ethylacetate and extracted with a 1N aqueous solution of hydrochloric acid.The extract was neutralized with a saturated aqueous solution of sodiumbicarbonate, then extracted with ethyl acetate, dried, and the solventswere eliminated under reduced pressure to obtain 10 g of crude[trans(±)]2,3-dihydro-1-[methyl(benzyl)-amino]-3,3-dimethyl-1H-inden-2-olwhich was purified by chromatography over silica (eluent:n-hexane-ethylacetate 8-2) to obtain 8.86 g of the product.

STEP B: Mesylate of [trans(±)]1,1-dimethyl-3-benzylmethylamino-2-indanol

8.7 g of the product of Step A were cooled to -20° C. in 80 ml ofmethylene chloride and 13 ml of triethylamine, and 4.85 ml of methanesulfonyl chloride in 24 ml of methylene chloride were added dropwise.After stirring for 30 minutes at -20° C., the temperature was allowed toreturn to +3° C. and cold water was added. The organic phase wasseparated and washed with water, then dried and the solvents wereeliminated under reduced pressure to obtain 13 g of mesylate of[trans(±)]1,1-dimethyl-3-benzylmethylamino-2-indanol which was used asis in the following step.

STEP C: [Trans(±)]1,1-dimethyl-2-benzylmethylamino-3-pyrrolidine-indane

At ambient temperature, 30 ml of pyrrolidine in 30 ml of distilled waterwere added to 13 g of the product of Step B and the mixture was heatedfor 17 hours at 75° C., then cooled to ambient temperature. Excesspyrrolidine was evaporated off under reduced pressure and the reactionmedium was saturated with sodium chloride, then extracted with ethylacetate. The extracts were dried, and the solvents were eliminated underreduced pressure to obtain 13.5 g of crude product which was purified bychromatography over silica (eluent:n-hexane-ethyl acetate 8-2) to obtain8.7 g of[trans(±)]1,1-dimethyl-2-benzylmethylamino-3-pyrrolidine-indane.

STEP D: [Trans(±)]1,1-dimethyl-2-methylamino-3-pyrrolidino-indane

2.5 g of the product of Step C in 56.5 ml of methanol, and 4 ml of 37%hydrochloric acid were hydrogenated for 14 hours (p=185 mbar) in thepresence of 1.7 g of activated charcoal with 10% palladium. Afterevaporating off the methanol under reduced pressure, taking up withwater and neutralizing with triethylamine, extraction was done withethyl acetate. The extracts were dried and the solvents were eliminatedunder reduced pressure to obtain 0.7 g of residue which was taken up in5 ml of water. 6 ml of 32% sodium hydroxide were added, and extractionwas done with ethyl acetate. The extracts were washed with an aqueoussolution of sodium chloride, then dried and concentrated to drynessunder reduced pressure to obtain 0.64 g of[trans(±)]1,1-dimethyl-2-methyl-amino-3-pyrrolidine-indane which wasused as is for the following step.

STEP E:[Trans(±)]N-[2,3-dihydro-1,1-dimethyl-3-(1-pyrrolidinyl-1H-inden-2-yl]-N-methyl-4-nitrobenzene-acetamideand its hydrochloride

Using the procedure of Step C of Example 1, 0.386 g of the product ofStep D and 0.371 g of p-nitrophenyl acetic acid were reacted to obtainafter chromatography of the crude product over silica (eluent:ethylacetate with 1% of triethylamine) 0.585 g of the expected product in theform of its base, then 0.483 g of its hydrochloride melting at 209° C.

Analysis: C₂₄ H₂₉ N₃ O₃, HCl: 443.97.

    ______________________________________                                        Calculated:                                                                           % C 64.92  % H 6.81  % N 9.46                                                                              % Cl 7.98                                Found:  64.9       6.9       9.5     7.8                                      ______________________________________                                    

EXAMPLE 29[Trans(±)]3,4-dichloro-N-[2,3-dihydro-1,1-dimethyl-3-(1-pyrrolidinyl)-1H-inden-2-yl]-N-methyl-benzene-acetamideand its trans butane dioate

Using the procedure of Step D of Example 2, 0.570 g of the product ofStep D of Example 28 and 0.668 g of 3,4-dichlorophenyl acetic acid werereacted to obtain 1.232 g of the expected product in the form of itsbase, then 0.502 g of its fumarate melting at 170° C.

Analysis: C₂₄ H₂₈ Cl₂ N₂ O, C₄ H₄ O₄ : 547.483.

    ______________________________________                                        Calculated:                                                                           % C 61.43  % H 5.89  % N 5.12                                                                              % Cl 12.93                               Found:  61.3       6.0       5.0     12.9                                     ______________________________________                                    

EXAMPLE 30[Trans(±)]N-[4-bromo-2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-3,4-dichloro-N-methyl-benzene-acetamideand its hydrochloride STEP A: 3-bromo-1aH-indeno[1,2-b]oxirene

Using the procedure of Step A of Example 26, 13.2 g of 7-bromo-1H-indenewere reacted to obtain 17.32 g of 3-bromo-1aH-indeno[1,2-b]oxirene whichwas used as is for the following step.

STEP B: [Trans(±)]4-bromo-2,3-dihydro-1-(1-pyrrolidinyl)-1H-inden-2-oland its hydrochloride

Using the procedure of Step B of Example 26, the product of Step A wasreacted to obtain 7.88 g of crude product which was converted into itshydrochloride with 16 ml of a 1.68N ethanol solution of hydrogenchloride. The product melted at 229° C. (decomposes).

STEP C:[Trans(±)]4-bromo-2,3-dihydro-N-methyl-2-(1-pyrrolidinyl)-1H-inden-1-amineand its hydrochloride

Using the procedure of Steps C and D of Example 26, the product of StepB was reacted to obtain 4.12 g of crude product in the form of the basewhich was converted into the hydrochloride with 4 ml of an ethanolsolution of hydrogen chloride (about 6.6N) to obtain 3.82 g of thehydrochloride melting at about 240° C.

STEP D:[Trans(±)]N-[4-bromo-2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-3,4-dichloro-N-methyl-benzene-acetamideand its hydrochloride

Using the procedure of Step C of Example 1, 0.533 g of3,4-dichlorophenyl acetic acid, 0.421 g of carbonyldiimidazole and 0.735g of the hydrochloride of Step C were reacted to obtain 0.876 g ofproduct in the form of the base, then 0.587 g of its hydrochloridemelting at 208° C.

Analysis: C₂₂ H₂₃ BrCl₂ N₂ O, HCl: 547.483.

    ______________________________________                                        Calculated:                                                                           % C    % H 4.66 % N 5.40                                                                             % Cl 20.50                                                                            % Br 15.40                                     50.94                                                                 Found:  51.1   4.6      5.3    20.3    15.4                                   ______________________________________                                    

EXAMPLE 31[Trans(±)]N-[5-chloro-2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-3,4-dichloro-N-methyl-benzene-acetamideand its hydrochloride STEP A:[Trans(±)]4-chloro-1aH-indeno[1,2-b]oxirene

Using the procedure of Step A of Example 26, 10.05 g of6-chloro-1H-indene were reacted to obtain 14.2 g of[trans(±)]4-chloro-1aH-indeno[1,2-b]oxirene which was used as is for thefollowing step.

STEP B: [Trans(±)]5-chloro-2,3-dihydro-1-(1-pyrrolidinyl)-1H-inden-2-oland its hydrochloride

Using the procedure of Step B of Example 26, the product of Step A wasreacted to obtain 4.48 g of the expected product in the form of a basewhich was converted into its hydrochloride with 11 ml of a 0.68N ethanolsolution of hydrogen chloride to obtain 3.52 g of the expectedhydrochloride melting at 159° C.

STEP C:[Trans(±)]5-chloro-2,3-dihydro-N-methyl-2-(1-pyrrolidinyl)-1H-inden-1-amineand its oxalate

Using the procedure of Steps C and D of Example 26, the product of StepB was reacted to obtain 3.83 g of the expected product in the form of abase, then 4.38 g of oxalate by the addition of 2.3 g of dihydratedoxalic acid melting about 165° C.

STEP D:[Trans(±)]N-[5-chloro-2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-3,4-dichloro-N-methyl-benzene-acetamideand its hydrochloride

Using the procedure of Step C of Example 1, 0.533 g of3,4-dichlorophenyl acetic acid, 0.421 g of carbonyldiimidazole and 0.772g of the oxalate of Step C were reacted to obtain 0.940 g of theexpected product in the form of a base, then 0.760 g of hydrochloridemelting at 228° C.

Analysis: C₂₂ H₂₃ Cl₃ N₂ O, HCl: 474.26.

    ______________________________________                                        Calculated:                                                                           % C 55.72  % H 5.10  % N 5.91                                                                              % Cl 22.90                               Found:  56.0       5.2       5.9     29.6                                     ______________________________________                                    

EXAMPLE 32

Tablets were prepared containing 200 mg of the product of Example 1 andsufficient excipient of lactose, talc, starch and magnesium stearate fora final weight of 800 mg.

EXAMPLE 33

An injectable solution (intra-muscular route) was prepared containing 50mg of the product of Example 25 and sufficient sterile solvent for avolume of 5 ml.

PHARMACOLOGICAL STUDY 1) Liaison with the opiated receptor K in vitro

Membrane residue prepared from the cerebella of guinea-pigs preserved at-30° C. (possibly up to about 30 days) were used and these residues weresuspended in Tris pH 7.7 buffer. Fractions of 2 ml were distributed inhaemolysis tubes and 9³ H ethylketocyclazocine 1 nM was added togetherwith the product to be studied. The product was first tested at 5×10⁻⁶ M(in triplicate). When the product tested displaced by more than 50% theradioactivity bonded specifically to the receptor, it was again testedin a range of 7 doses to determine the dose which inhibited by 50% theradioactivity bonded specifically to the receptor. In this way, the 50%inhibiting concentration was determined. The non-specific liaison wasdetermined by addition of the product known by the name U-50488 H (Lahtiet al. 1982, Life Sci. 31, 2257) at 10⁻⁵ M (in triplicate). It was thenincubated at 25° C. for 40 minutes, replaced on the water-bath at 0° C.for 5 minutes, filtered under vacuum, rinsed with the Tris pH 7.7buffer, and the radioactivity was counted in the presence ofscintillating Trition.

The result was expressed in the following Table directly as 50%inhibiting concentration (IC₅₀), (i.e., as the concentration of theproduct studied, expressed in nM, necessary to displace 50% of thespecific radioactivity fixed on the receptor studied.

    ______________________________________                                        Product of example                                                                             IC.sub.50 in nM                                              ______________________________________                                         1               1.8                                                           5               3                                                             6               7.5                                                           8               7.1                                                           9               2.7                                                          14               3.8                                                          16               5                                                            22               7.1                                                          25               2.2                                                          29               5.6                                                          ______________________________________                                    

2) Analgesic activity

Female mice weighing 22 to 24 g were placed one by one on a copper platemaintained at 56° C. and the reaction to the pain was seen by the animallicking its front paws. The time of this reaction was noted and only themice reacting in less than 8 seconds were retained. The animals weredistributed in homogeneous groups and treated with the product understudy administered orally, one group receiving only the vehicle. Thetime of reaction to the pain was again measured 30 to 60 minutes afterthe treatment. The active dose or AD₁₀₀ was the dose which increased thereaction time by 100% 30 minutes after the treatment, taking account ofthe variation of the reaction times of the control animals. For theproduct of Example 1, the AD₁₀₀ was 50 mg/kg.

3) Study of the hypotensive activity on the anaesthetized rat

Male Sprague Dawley (CR) rats were anaestherized intra-peritoneally with60 mg/kg of sodium pentobarbital and a jugular vein was catheterized forinjection of the product, and a carotid artery was catheterized toregister the arterial pressure. The product under test was dissolved in10% of ethanol and then was injected at a volume of 1 ml/kg. Thepressure was noted at times of 5 minutes and 30 minutes after theinjection of the product. The following Table indicates the variationsexpressed as a percentage of the arterial pressure after administrationof the product under test to the arterial pressure of the initialcontrol.

Results:

    ______________________________________                                        Product of                                                                              dose      5 min. after                                                                             30 min. after                                  example   mg/kg     administration                                                                           administration                                 ______________________________________                                        1         10        -13        -19                                                       1        -19        -23                                            4         10        -26        -14                                            5         10        -25        -10                                                       1        -20        -20                                            8          1        -25        -27                                            14         1        -22        -26                                            9         10        -32        -31                                            ______________________________________                                    

4) Measurement of the diuretic activity

Male rats of Sprague Dawley strain weighing 180 to 200 g were not fedfor 17 hours before the test, but received water ad libitum. Groups of 8animals were set up for each dose tested and the rats received theproduct under test or its vehicle orally. The urinary volume wasmeasured every hour for the 5 hours following the administration of theproduct. At the end of this period, the urines were collected and theactivity of the product was expressed as a percentage of variationcalculated on the urinary volume corresponding to the period t_(1h)-t_(5h). The following results were obtained:

    ______________________________________                                        Product of   dose    percentage of variation                                  example      mg/kg   of the urinary volume                                    ______________________________________                                        1            5       +188                                                     1            5       +190                                                     8            5       +130                                                                  2.5     +124                                                     14           5        +68                                                     9            10       +74                                                     ______________________________________                                    

5) Anti-arrythmic activity in the rat

Male rats weighing 300 to 350 g anaesthetized intra-peritoneally with1.20 g/kg of urethane were tracheotomized and submitted to artificialrespiration (40 to 50 insufflations of 3 ml/minute). Needles wereimplanted sub-cutaneously to register the electro-cardiagram of the ratson the DII derivation signal. The product under test was administeredintravenously and 5 minutes after the administration of the product, thejugular vein of the rats was perfused with 10 μg/kg from 0.2 ml of anaconitine solution and the time of appearance of disturbances of thecardiac rhythm was noted. The results expressed as a percentage of theextension of the time of appearance of the disturbances of the cardiacrhythm in relation to the controls and as a function of the dose of theproduct tested are in the following Table which show that the testedproducts of the application are endowed with good anti-arrythmicproperties.

    ______________________________________                                                                 Percentage of                                                         Dose    extension of                                         Product of example                                                                             mg/kg   time                                                 ______________________________________                                        1                10      +31.4                                                                  5      +20.6                                                5                10      +15.6                                                8                 5      +23                                                  9                10      +34.6                                                                  5      +32                                                  ______________________________________                                    

Various modifications of the products and method of the invention may bemade without departing from the spirit or scope thereof and it is to beunderstood that the invention is intended to be limited only as definedin the appended claims.

What we claim is:
 1. A compound selected from the group consisting ofenantiomers and diastereoisomer forms and mixtures thereof of theformula ##STR25## wherein R₁ and R₂ together with the carbon atom towhich they are attached form tetrahydropyran R₆ is selected from thegroup consisting of hydrogen, halogen and alkyl and alkoxy of 1 to 5carbon atoms, one of A and B has the formula ##STR26## and the other ispyrrolidinyl, R is hydrogen or alkyl of 1 to 5 carbon atoms, Z isselected from the group consisting of --(CH₂)_(n) --, --CH₂ O-- andbranched alkylene of 2 to 8 carbon atoms, n is an integer from 0 to 5,X, X' and X" are individually selected from the group consisting ofhydrogen, alkyl and alkoxy of 1 to 5 carbon atoms, halogen, --OH, --CF₃,--NO₂, --NH₂, mono- and dialkylamino of 1 to 4 alkyl carbon atoms andsulfamino and their non-toxic, pharmaceutically acceptable acid additionsalts.
 2. A compound of claim 1 wherein A and B have a transconfiguration.
 3. A compound of claim 1 wherein R is hydrogen, methyl orethyl and Z is --(CH₂)_(n) --, ##STR27## or --CH₂ O-- and n is 0 or 1.4. A compound of claim 1 wherein X, X' and X" are individually selectedfrom the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy,--NO₂, --CF₃, Cl and sulfamino.
 5. A compound of claim 1 selected fromthe group consisting of[trans(±)]3,4-dichloro-N-[2,2',3,3',5',6'-hexahydro-2-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-3-yl]-N-methyl-benzene-acetamideand its hydrochloride and (E) butenedioate of[trans(±)]3,4-dichloro-N-[2,2',3,3',5',6'-hexahydro-3-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-2-yl]-N-methyl-benzene-acetamide.6. A central analgesic composition comprising a central analgesicallyeffective amount of a compound of claim 1 and an inert pharmaceuticalcarrier.
 7. A composition of claim 6 wherein in the compound of formula1, A and B have a trans configuration.
 8. A composition of claim 6wherein in the compound of formula 1, R is hydrogen, methyl or ethyl andZ is --(CH₂)_(n) --, ##STR28## or --CH₂ O-- and n is 0 or
 1. 9. Acomposition of claim 6 wherein in the compound of formula 1, X, X' andX" are individually selected from the group consisting of hydrogen,methyl, ethyl, methoxy, ethoxy, --NO₂, --CF₃, --Cl and sulfamino.
 10. Acomposition of claim 6 wherein the active compound is selected from thegroup consisting of[trans(±)]3,4-dichloro-N-[2,2',3,3',5',6-hexahydro-2-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-3-yl]-N-methyl-benzene-acetamideand its hydrochloride and (E) butenedioate of[trans(±)]3,4-dichlor-N-[2,2',3,3',5',6'-hexahydro-3-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-2-yl]-N-methyl-benzene-acetamide.11. A method of inducing central analgesic activity in warm-bloodedanimals comprising administering to warm-blooded animals ananalgesically effective amount of a compound of claim
 1. 12. A method ofclaim 11 wherein A and B have a trans configuration.
 13. A method ofclaim 11 wherein R is hydrogen, methyl or ethyl and Z is --(CH₂)_(n) --,##STR29## or --CH₂ O-- and n is 0 or
 1. 14. A method of claim 11 whereinX, X' and X" are individually selected from the group consisting ofhydrogen, methyl, ethyl, methoxy, ethoxy, --NO₂, --CF₃, Cl andsulfamino.
 15. A method of claim 11 wherein the active compound isselected from the group consisting of[trans(±)]3,4-dichloro-N-[2,2',3,3',5',6'-hexahydro-2-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-3-yl]-N-methyl-benzene-acetamideand its hydrochloride and (E) butenedioate of[trans(±)]3,4-dichloro-N-[2,2',3,3',5',6'-hexahydro-3-(1-pyrrolidinyl)-spiro[1H-inden-1,4'-(4H)-pyran]-3-yl]-N-methyl-benzene-acetamide.16. A method of inducing diuresis activity in warm-blooded animalscomprising administering to warm-blooded animals a diureticallyeffective amount of a compound of claim
 1. 17. A method of treatingarrythmia in warm-blooded animals comprising administering towarm-blooded animals an anti-arrythmically effective amount of acompound of claim 1.